Compounds and compositions for delivering active agents

ABSTRACT

Modified amino acid compounds useful in the delivery of active agents are provided. Methods of administration and preparation are provided as well.

[0001] This application is a continuation-in-part of:

[0002] (a) Is a continuation-in-part of PCT Application Serial No.PCT/US94/04560, filed Apr. 22, 1994, which is a continuation-in-part ofU.S. application Ser. No. 08/051,019, filed Apr. 22, 1993, and of U.S.application Ser. No. 08/205,511, filed on Mar. 2, 1994; and

[0003] (b) application Ser. No. 08/231,622, filed Apr. 22, 1994.

FIELD OF THE INVENTION

[0004] The present invention relates to compounds for delivering activeagents, and particularly biologically active agents such as, forexample, bioactive peptides and the like. These compounds are used ascarriers to facilitate the delivery of a cargo to a target. The carriersare modified amino acids and are well suited to form non-covalentmixtures with biologically-active agents for oral administration toanimals. Methods for the preparation and for the administration of suchcompositions are also disclosed.

BACKGROUND OF THE INVENTION

[0005] Conventional means for delivering active agents are oftenseverely limited by biological, chemical, and physical barriers.Typically, these barriers are imposed by the environment through whichdelivery occurs, the environment of the target for delivery, or thetarget itself.

[0006] Biologically active agents are particularly vulnerable to suchbarriers. For example in the delivery to animals of pharmacological andtherapeutic agents, barriers are imposed by the body. Examples ofphysical barriers are the skin and various organ membranes that must betraversed before reaching a target. Chemical barriers include, but arenot limited to, pH variations, lipid bi-layers, and degrading enzymes.

[0007] These barriers are of particular significance in the design oforal delivery systems. Oral delivery of many biologically active agentswould be the route of choice for administration to animals if not forbiological, chemical, and physical barriers such as varying pH in thegastro-intestinal (GI) tract, powerful digestive enzymes, and activeagent impermeable gastro-intestinal membranes. Among the numerous agentswhich are not typically amenable to oral administration are biologicallyactive peptides, such as calcitonin and insulin; polysaccharides, and inparticular mucopolysaccharides including, but not limited to, heparin;heparinoids; antibiotics; and other organic substances. These agents arerapidly rendered ineffective or are destroyed in the gastrointestinaltract by acid hydrolysis, enzymes, or the like.

[0008] Earlier methods for orally administering vulnerablepharmacological agents have relied on the co-administration of adjuvants(e.g., resorcinols and non-ionic surfactants such as polyoxyethyleneoleyl ether and n-hexadecylpolyethylene ether) to increase artificiallythe permeability of the intestinal walls, as well as theco-administration of enzymatic inhibitors (e.g., pancreatic trypsininhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibitenzymatic degradation.

[0009] Liposomes have also been described as drug delivery systems forinsulin and heparin. See, for example, U.S. Pat. No. 4,239,754; Patel etal. (1976), FEBS Letters, Vol. 62, pg. 60; and Hashimoto et al. (1979),Endocrinology Japan, Vol. 26, pg. 337.

[0010] However, broad spectrum use of such drug delivery systems isprecluded because: (1) the systems require toxic amounts of adjuvants orinhibitors; (2) suitable low molecular weight cargos, i.e. activeagents, are not available; (3) the systems exhibit poor stability andinadequate shelf life; (4) the systems are difficult to manufacture; (5)the systems fail to protect the active agent (cargo); (6) the systemsadversely alter the active agent; or (7) the systems fail to allow orpromote absorption of the active agent.

[0011] More recently, microspheres of artificial polymers of mixed aminoacids (proteinoids) have been used to deliver pharmaceuticals. Forexample, U.S. Pat. No. 4,925,673 describes drug-containing proteinoidmicrosphere carriers as well as methods for their preparation and use.These proteinoid microspheres are useful for the delivery of a number ofactive agents.

[0012] There is still a need in the art for simple, inexpensive deliverysystems which are easily prepared and which can deliver a broad range ofactive agents.

SUMMARY OF THE INVENTION

[0013] Compounds useful in the delivery of active agents are provided.These compounds include

[0014] or salts thereof.

[0015] Compositions comprising at least one biologically active agentand at least one of the compounds above are also provided. Furthercontemplated by the present invention are dosage unit forms that includethese compositions.

[0016] Also contemplated is a method for preparing these compositionswhich comprises mixing at least one active agent with at least onecompound as described above, and optionally, a dosing vehicle.

[0017] In an alternative embodiment, these non-toxic compounds areorally administered to animals as part of a delivery system by blendingor mixing the compounds with an active agent prior to administration.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The specific compounds of the present invention or salts thereofsuch as, for example, sodium salts, may be used to deliver variousactive agents through various biological, chemical, and physicalbarriers. These compounds are particularly suited for delivering activeagents which are subject to environmental degradation. The compounds andcompositions of the subject invention are particularly useful fordelivering or administering biologically-active agents to any animalssuch as birds; mammals, such as primates and particularly humans; andinsects.

[0019] Other advantages of the present invention include the use of easyto prepare, inexpensive raw materials. The compositions and theformulation methods of the present invention are cost effective, simpleto perform, and amenable to industrial scale up for commercialproduction.

[0020] Amino acids, poly amino acids, and peptides, in modified form,may be used to deliver active agents including, but not limited to,biologically active agents such as for example, pharmacological andtherapeutic agents.

[0021] An amino acid is any carboxylic acid having at least one freeamine group and includes naturally occurring and synthetic amino acids.

[0022] Poly amino acids are either peptides or two or more amino acidslinked by a bond formed by other groups which can be linked, e.g. anester, anhydride, or an anhydride linkage. Special mention is made ofnon-naturally occurring poly amino acids and particularly non-naturallyoccurring hetero poly amino acids, i.e. polymers of mixed amino acids.

[0023] Peptides are two or more amino acids joined by a peptide bond.Peptides can vary in length from dipeptides with two amino acids to polypeptides with several hundred amino acids. See Chambers BiologicalDictionary, editor Peter M. B. Walker, Cambridge, England: ChambersCambridge, 1989, page 215. Special mention is made of di-peptides,tri-peptides, tetra-peptides, and penta-peptides.

[0024] The terms modified amino acids, modified poly amino acids, andmodified peptides are meant to include amino acids which have beenmodified or poly amino acids and peptides in which at least one aminoacid has been modified by acylating at least one free amine group withan acylating agent which reacts with at least one of the free aminegroups present.

Modified Amino Acids

[0025] Several of the compounds of the present invention are broadlyrepresented by one of formula XLVI or XLVII below:

Ar—Y—(R¹)_(n)—OH   XLVI

[0026] wherein Ar is a substituted or unsubstituted phenyl or naphthyl;

[0027] has the formula

[0028] wherein:

[0029] R² is C₁ to C₂₄ alkyl, C₁ to C₂₄ alkenyl, phenyl, naphthyl, (C₁to C₁₀ alkyl) phenyl, (C₁ to C₁₀ alkenyl) phenyl, (C₁ to C₁₀ alkyl)naphthyl, (C₁ to C₁₀ alkenyl) naphthyl, phenyl (C₁ to C₁₀ alkyl), phenyl(C₁ to C₁₀ alkenyl), naphthyl (C₁ to C₁₀ alkyl), and naphthyl (C₁ to C₁₀alkenyl);

[0030] R² is optionally substituted with C₁ to C₄ alkyl, C₁ to C₄alkenyl, C₁ to C₄ alkoxy, —OH, —SH and —CO₂R⁴ or any combinationthereof;

[0031] R⁴ is hydrogen, C₁ to C₄ alkyl or C₁ to C₄ alkenyl;

[0032] R² is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof; and

[0033] R³ is hydrogen, C₁ to C₄ alkyl or C₁ to C₄ alkenyl; or

[0034] wherein: R⁵ is (i) C₃-C₁₀ cycloalkyl, optionally substituted withC₁-C₇ alkyl, C₂-C₇ alkenyl, C₁-C₇ alkoxy, hydroxy, phenyl, phenoxy or—CO₂R⁸, wherein R⁸ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; or

[0035] (ii) C₁-C₆ alkyl substituted with C₃-C₁₀ cycloalkyl;

[0036] R⁶ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl;

[0037] R is C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkenyl, phenyl, naphthyl, (C₁-C₁₀ alkyl) phenyl, (C₂-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl) naphthyl, (C₂-C₁₀ alkenyl) naphthyl, phenyl(C₁-C₁₀ alkyl), phenyl (C₂-C₁₀ alkenyl), naphthyl (C₁-C₁₀ alkyl) ornaphthyl (C₂-C₁₀ alkenyl);

[0038] R⁷ being optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl,C₁-C₄ alkoxy, —OH, —SH, —CO₂R⁹, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,heterocycle having 3-10 ring atoms wherein the hetero atom is one ormore of N, O, S or any combination thereof, aryl, (C₁-C₁₀ alk)aryl,ar(C₁-C₁₀ alkyl), or any combination thereof;

[0039] R⁷ being optionally interrupted by oxygen, nitrogen, sulfur, orany combination thereof; and

[0040] R⁹ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl.

[0041] Special mention is made of compounds I-XLV above.

[0042] The modified amino acids of compounds I-XLV may be prepared byreacting single amino acids, mixtures of two or more amino acids, aminoacid esters, or amino acid amides, with an amine modifying agent whichreacts with free amino moieties present in the amino acids to formamides.

[0043] Modified amino acids are typically prepared by modifying theamino acids or an ester thereof. Many of these compounds are prepared byacylation with acylating agents having the formula

[0044] wherein: R¹⁰ is the appropriate radical to yield the modificationindicated in the final product as would be within the skill of the artbased upon the detailed disclosure herein, and Y is a leaving group.Typical leaving groups include, but are not limited to, halogens suchas, for example, chlorine, bromine, and iodine. Additionally, thecorresponding anhydrides are suitable acylating agents.

[0045] Many of the compounds of the present invention can be readilyprepared and modified by methods within the skill of those in the artbased upon the present disclosure. For example, the modified amino acidcompounds above may be prepared by reacting the single amino acid withthe appropriate acylating agent or an amine modifying agent which reactswith free amino moiety present in the amino acids to form amides.Protecting groups may be used to avoid unwanted side reactions as wouldbe known to those skilled in the art.

[0046] For example, the amino acid can be dissolved in aqueous alkalinesolution of a metal hydroxide, e.g., sodium or potassium hydroxide, andheated at a temperature ranging between about 5° C. and about 70° C.,preferably between about 10° C. and about 40° C., for a period rangingbetween about 1 hour and about 4 hours, preferably about 2.5 hours. Theamount of alkali employed per equivalent of NH₂ groups in the amino acidgenerally ranges between about 1.25 and about 3 mmole, preferablybetween about 1.5 and about 2.25 mmole per equivalent of NH₂. The pH ofthe solution generally ranges between about 8 and about 13, preferablyranging between about 10 and about 12.

[0047] Thereafter, the appropriate amino modifying agent is added to theamino acid solution while stirring. The temperature of the mixture ismaintained at a temperature generally ranging between about 5° C. andabout 70° C., preferably between about 10° C. and about 40° C., for aperiod ranging between about 1 and about 4 hours. The amount of aminomodifying agent employed in relation to the quantity of amino acid isbased on the moles of total free NH₂ in the amino acid. In general, theamino modifying agent is employed in an amount ranging between about 0.5and about 2.5 mole equivalents, preferably between about 0.75 and about1.25 equivalents, per molar equivalent of total NH₂ group in the aminoacid.

[0048] The reaction is quenched by adjusting the pH of the mixture witha suitable acid, e.g., concentrated hydrochloric acid, until the pHreaches between about 2 and about 3. The mixture separates on standingat room temperature to form a transparent upper layer and a white oroff-white precipitate. The upper layer is discarded, and the modifiedamino acid is collected from the lower layer by filtration ordecantation. The crude modified amino acid is then dissolved in water ata pH ranging between about 9 and about 13, preferably between about 11and about 13. Insoluble materials are removed by filtration and thefiltrate is dried in vacuo. The yield of modified amino acid generallyranges between about 30 and about 60%, and usually about 45%.

[0049] If desired, amino acid esters, such as, for example methyl orethyl esters of amino acid compounds, may be used to prepare themodified amino acids of the invention. The amino acid ester, dissolvedin a suitable organic solvent such as dimethylformamide or pyridine, isreacted with the appropriate amino modifying agent at a temperatureranging between about 5° C. and about 70° C., preferably about 25° C.,for a period ranging between about 7 and about 24 hours. The amount ofamino modifying agent used relative to the amino acid ester is the sameas described above for amino acids.

[0050] Thereafter, the reaction solvent is removed under negativepressure and the ester functionality is removed by hydrolyzing themodified amino acid ester with a suitable alkaline solution, e.g. 1Nsodium hydroxide, at a temperature ranging between about 50° C. andabout 80° C., preferably about 70° C., for a period of time sufficientto hydrolyze off the ester group and form the modified amino acid havinga free carboxyl group. The hydrolysis mixture is then cooled to roomtemperature and acidified, e.g. aqueous 25% hydrochloric acid solution,to a pH ranging between about 2 and about 2.5. The modified amino acidprecipitates out of solution and is recovered by conventional means suchas filtration or decantation.

[0051] The modified amino acid may be purified by recrystallization orby fractionation on solid column supports. Suitable recrystallizationsolvent systems include acetonitrile, methanol and tetrahydrofuran.Fractionation may be performed on a suitable solid column supports suchas alumina, using methanol/n-propanol mixtures as the mobile phase;reverse phase column supports using trifluoroacetic acid/acetonitrilemixtures as the mobile phase; and ion exchange chromatography usingwater as the mobile phase. When anion exchange chromatography isperformed, preferably a subsequent 0-500 mM sodium chloride gradient isemployed.

[0052] Active Agents

[0053] Active agents suitable for use in the present invention includebiologically active agents, chemically active agents, including, but notlimited to, fragrances, as well as other active agents such as, forexample, cosmetics.

[0054] Biologically active agents include, but are not limited to,pesticides, pharmacological agents, and therapeutic agents. For example,biologically active agents suitable for use in the present inventioninclude, but are not limited to, peptides, and particularly smallpeptides; hormones, and particularly hormones which by themselves do notor only pass slowly through the gastro-intestinal mucosa and/or aresusceptible to chemical cleavage by acids and enzymes in thegastro-intestinal tract; polysaccharides, and particularly mixtures ofmuco-polysaccharides; carbohydrates; lipids; or any combination thereof.Further examples include, but are not limited to, human growth hormones;bovine growth hormones; growth releasing hormones; interferons;interleukin-1; insulin; heparin, and particularly low molecular weightheparin; calcitonin; erythropoietin; atrial naturetic factor; antigens;monoclonal antibodies; somatostatin; adrenocorticotropin, gonadotropinreleasing hormone; oxytocin; vasopressin; cromolyn sodium (sodium ordisodium chromoglycate); vancomycin; desferrioxamine (DFO);anti-microbials, including, but not limited to anti-fungal agents; orany combination thereof.

Delivery Systems

[0055] The compositions of the present invention may include one or moreactive agents.

[0056] In one embodiment, compounds I-XLV or poly amino acids orpeptides that include at least one of these compounds may be useddirectly as a drug delivery carrier by simply mixing one or morecompound, poly amino acid or peptide with the active ingredient prior toadministration.

[0057] In an alternative embodiment, the compounds, poly amino acids, orpeptide may be used to form microspheres containing the active agent.These compounds, poly amino acids, or peptides are particularly usefulfor the oral administration of certain biologically-active agents, e.g.,small peptide hormones, which, by themselves, do not pass or only passslowly through the gastro-intestinal mucosa and/or are susceptible tochemical cleavage by acids and enzymes in the gastrointestinal tract.

[0058] If the modified amino acids, poly amino acids, or peptides are tobe converted into microspheres, the mixture is optionally heated to atemperature ranging between about 20 and about 50° C., preferably about40° C., until the modified amino acid(s) dissolve. The final solutioncontains between from about 1 mg and to about 2000 mg of compound, polyamino acid, or peptide per mL of solution, preferably between about 1and about 500 mg per mL. The concentration of active agent in the finalsolution varies and is dependent on the required dosage for treatment.When necessary, the exact concentration can be determined by, forexample, reverse phase HPLC analysis.

[0059] When the compounds, poly amino acids, or peptides are used toprepare microspheres, another useful procedure is as follows: Compounds,poly amino acids, or peptides are dissolved in deionized water at aconcentration ranging between about 75 and about 200 mg/ml, preferablyabout 100 mg/ml at a temperature between about 25° C. and about 60° C.,preferably about 40° C. Particulate matter remaining in the solution maybe removed by conventional means such as filtration.

[0060] Thereafter, the compound, poly amino acid, or peptide solution,maintained at a temperature of about 40° C., is mixed 1:1 (V/V) with anaqueous acid solution (also at about 40° C.) having an acidconcentration ranging between about 0.05 N and about 2 N, preferablyabout 1.7 N. The resulting mixture is further incubated at 40° C. for aperiod of time effective for microsphere formation, as observed by lightmicroscopy. In practicing this invention, the preferred order ofaddition is to add the compound, poly amino acid, or peptide solution tothe aqueous acid solution.

[0061] Suitable acids for microsphere formation include any acid whichdoes not

[0062] (a) adversely effect the modified amino acids, poly amino acids,or peptides e.g., initiate or propagate chemical decomposition;

[0063] (b) interfere with microsphere formation;

[0064] (c) interfere with microsphere incorporation of the cargo; and

[0065] (d) adversely interact with the cargo.

[0066] Preferred acids for use in this aspect include acetic acid,citric acid, hydrochloric acid, phosphoric acid, malic acid and maleicacid.

[0067] A microsphere stabilizing additive may be incorporated into theaqueous acid solution or into the compound or cargo solution prior tothe microsphere formation process. With some drugs the presence of suchadditives promotes the stability and/or dispersibility of themicrospheres in solution.

[0068] The stabilizing additives may be employed at a concentrationranging between about 0.1 and 5% (w/v), preferably about 0.5% (w/v).Suitable, but non-limiting, examples of microsphere stabilizingadditives include gum acacia, gelatin, methyl cellulose, polyethyleneglycol, and polylysine. The preferred stabilizing additives are gumacacia, gelatin and methyl cellulose.

[0069] Under the above conditions, the compound molecules, poly aminoacids, or peptides form hollow or solid matrix type microspheres whereinthe cargo is distributed in a carrier matrix or capsule typemicrospheres encapsulating liquid or solid cargo. If the compound, polyamino acid, or peptide microspheres are formed in the presence of asoluble material, e.g., a pharmaceutical agent in the aforementionedaqueous acid solution, this material will be encapsulated within themicrospheres. In this way, one can encapsulate pharmacologically activematerials such as peptides, proteins, and polysaccharides as well ascharged organic molecules, e.g., antimicrobial agents, which normallyhave poor bioavailability by the oral route. The amount ofpharmaceutical agent which may be incorporated by the microsphere isdependent on a number of factors which include the concentration ofagent in the solution, as well as the affinity of the cargo for thecarrier. The compound, poly amino acid, or peptide microspheres do notalter the physiological and biological properties of the active agent.Furthermore, the encapsulation process does not alter thepharmacological properties of the active agent. Any pharmacologicalagent can be incorporated within the microspheres. The system isparticularly advantageous for delivering chemical or biological agentswhich otherwise would be destroyed or rendered less effective byconditions encountered within the body of the animal to which it isadministered, before the microsphere reaches its target zone (i.e., thearea in which the contents of the microsphere are to be released) andfor delivering pharmacological agents which are poorly absorbed in thegastro-intestinal tract. The target zones can vary depending upon thedrug employed.

[0070] The particle size of the microsphere plays an important role indetermining release of the active agent in the targeted area of thegastro-intestinal tract. The preferred microspheres have diametersbetween about ≦0.1 microns and about 10 microns, preferably betweenabout 0.5 microns and about 5 microns. The microspheres are sufficientlysmall to release effectively the active agent at the targeted areawithin the gastro-intestinal tract such as, for example, between thestomach and the jejunum. Small microspheres can also be administeredparenterally by being suspended in an appropriate carrier fluid (e.g.,isotonic saline) and injected directly into the circulatory system,intramuscularly or subcutaneously. The mode of administration selectedwill vary, of course, depending upon the requirement of the active agentbeing administered. Large amino acid microspheres (>50 microns) tend tobe less effective as oral delivery systems.

[0071] The size of the microspheres formed by contacting compounds, polyamino acids, or peptides with water or an aqueous solution containingactive agents can be controlled by manipulating a variety of physical orchemical parameters, such as the pH, osmolarity or ionic strength of theencapsulating solution, size of the ions in solution and by the choiceof acid used in the encapsulating process.

[0072] The administration mixtures are prepared by mixing an aqueoussolution of the carrier with an aqueous solution of the activeingredient, just prior to administration. Alternatively, the carrier andthe biologically active ingredient can be admixed during themanufacturing process. The solutions may optionally contain additivessuch as phosphate buffer salts, citric acid, acetic acid, gelatin andgum acacia.

[0073] Stabilizing additives may be incorporated into the carriersolution. With some drugs, the presence of such additives promotes thestability and dispersibility of the agent in solution.

[0074] The stabilizing additives may be employed at a concentrationranging between about 0.1 and 5% (W/V), preferably about 0.5% (W/V).Suitable, but non-limiting, examples of stabilizing additives includegum acacia, gelatin, methyl cellulose, polyethylene glycol, andpolylysine. The preferred stabilizing additives are gum acacia, gelatinand methyl cellulose.

[0075] The amount of active agent is an amount effective to accomplishthe purpose of the particular active agent. The amount in thecomposition typically is a pharmacologically or biologically effectiveamount. However, the amount can be less than a pharmacologically orbiologically effective amount when the composition is used in a dosageunit form, such as a capsule, a tablet or a liquid, because the dosageunit form may contain a multiplicity of carrier/biologically activeagent compositions or may contain a divided pharmacologically orbiologically effective amount. The total effective amounts can then beadministered in cumulative units containing, in total, pharmacologicallyor biologically active amounts of biologically or pharmacologicallyactive agent.

[0076] The total amount of active agent, and particularly biologicallyactive agent, to be used can be determined by those skilled in the art.However, it has surprisingly been found that with some biologicallyactive agents, the use of the presently disclosed carriers providesextremely efficient delivery. Therefore, lower amounts of biologicallyactive agent than those used in prior dosage unit forms or deliverysystems can be administered to the subject, while still achieving thesame blood levels and therapeutic effects.

[0077] The amount of carrier in the present composition is a deliveryeffective amount and can be determined for any particular carrier orbiologically active agent by methods known to those skilled in the art.

[0078] Dosage unit forms can also include any of excipients; diluents;disintegrants; lubricants; plasticizers; colorants; and dosing vehicles,including, but not limited to water, 1,2-propane diol, ethanol, oliveoil, or any combination thereof.

[0079] Administration of the present compositions or dosage unit formspreferably is oral or by intraduodenal injection.

[0080] The delivery compositions of the present invention may alsoinclude one or more enzyme inhibitors. Such enzyme inhibitors include,but are not limited to, compounds. such as actinonin or epiactinonin andderivatives thereof. These compounds have the formulas below:

[0081] Derivatives of these compounds are disclosed in U.S. Pat. No.5,206,384. Actinonin derivatives have the formula:

[0082] wherein R¹² is sulfoxymethyl or carboxyl or a substituted carboxygroup selected from carboxamide, hydroxyaminocarbonyl and alkoxycarbonylgroups; and R¹³ is hydroxyl, alkoxy, hydroxyamino or sulfoxyamino group.Other enzyme inhibitors include, but are not limited to, aprotinin(Trasylol) and Bowman-Birk inhibitor.

[0083] The compounds and compositions of the subject invention areuseful for administering biologically active agents to any animals suchas birds; mammals, such as primates and particularly humans; andinsects. The system is particularly advantageous for deliveringchemically or biologically active agents which would otherwise bedestroyed or rendered less effective by conditions encountered beforethe active agent its target zone (i.e. the area in which the activeagent of the delivery composition are to be released) and within thebody of the animal to which they are administered. Particularly, thecompounds and compositions of the present invention are useful in orallyadministering active agents, especially those which are not ordinarilyorally deliverable.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0084] The following examples illustrate the invention withoutlimitation.

EXAMPLE 1

[0085] Compound VI was prepared as follows:

[0086] Acetylsalicyloyl chloride (47.00 g, 0.24 mol, 1 equiv.) was addedportionwise to a mixture of 4-(4-aminophenyl)butyric acid (50.00 g, 0.28mol, 1.2 equiv.) in aqueous sodium hydroxide (2M, 300 mL). The reactionwas stirred at 25° C. for 2 hours, and the resultant solution wasacidified with aqueous hydrochloric acid (1 M) to pH 2.1. The resultantprecipitate was filtered, and was washed with aqueous hydrochloric acid(1 M, 3×100 mL) and water to give Compound VI as a pale pink solid(31.89 g, 52%).

[0087] Properties are listed below.

[0088]¹H NMR (300 MHz, DMSO-d₆) δ: 7.74 (1H, dd), 7.38 (2H, d), 7.21(3H, m), 6.67 (1H, m), 6.57 (1H, m), 2.48 (2H, t), 2.07 (2H, t), 1.71(2H, m). Anal. Calcd for C₁₇H₁₇NO₄: C, 68.20; H, 5.73; N, 4.70. Found:C, 68.22; H, 5.61; N, 4.66.

[0089] Similar procedures were used to prepare Compounds II, V, X, XIV,XVIII, XXII, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXIII, XXXIV, XXXV,XXXVI, XXXVII, XXXVIII, XL, XLI, XLII, and XLV.

[0090] Properties are listed below.

[0091] Compound II—¹H NMR (300 MHz, D₂O): δ 7.23(9H, m), 3.62(2H, s),2.50(2H, t), 2.17(2H, t), 1.73(2H, q)

[0092] Compound V—Anal. Calcd for C₁₇H₁₇NO₅: C, 64.74, H, 5.45, N, 4.44Found: C, 64.11, H, 5.46, N, 4.21. ¹H NMR (300 MHz, D₂O): δ 7.6 (1H,d),7.35 (2H,d), 7.15 (2H,m), 6.05 (1H,d), 2.5 (2H,m), 2.1 (2H,t), 1.7(2H,m)

[0093] Compound X—Anal. Calcd for C₂₃H₂₉NO₃: C, 75.16, H, 7.97, N, 3.79Found: C,74.90, H, 8.19, N, 3.38. ¹H NMR (300 MHz, CDCL₃): δ 7.35(2H,d), 7.27 (2H,d), 7.15 (2H,d), 6.95 (2H,d), 3.7 (1H,q), 2.6 (2H,t),2.5 (2H,d), 2.35 (2H,t), 1.9 (3H,m), 1.6 (3H,d), 0.9 (6H,d)

[0094] Compound XVIII—¹H NMR (300 MHz, DMSO-d₆): δ 12.1 (1H,s), 10.5(1H,s), 8.2 (1H,t), 8.0 (2H,m), 7.7 (3H,d), 7.6 (3H,d), 7.2 (2H,t), 3.3(1H,m), 2.6 (2H,t), 2.2 (2H,t), 1.8 (2H,t)

[0095] Compound XXII—Anal. Calcd for C₂₀H₂₃NO₃: C, 73.82, H, 7.12, N,4.30 Found: C, 73.53, H, 7.07, N, 4.28. ¹H NMR (300 MHz, DMSO-d₆): δ12.0 (1H,s), 10.0 (1H,s), 7.6 (2H,m), 7.4 (4H,m), 7.2 (1H,d), 7.0(2H,q), 3.55 (1H,t), 2.5 (4H,m), 2.2 (2H,q), 2.0 (1H,m), 1.7 (3H,m), 0.9(3H,t)

[0096] Compound XXV—Anal. Calcd for C₁₈H₁₈NO₃F: C, 68.56, H, 5.75, N,4.44 Found: C, 68.18, H, 5.63, N, 4.20. ¹H NMR (300 MH, DMSO-d₆): δ 12.1(1H,s), 10.1 (1H,s), 7.5 (2H,m), 7.35 (2H,m), 7.1 (4H,m), 3.6 (2H,s),2.5 (2H,t), 2.2 (2H,t), 1.75 (2H,m)

[0097] Compound XXVI—¹H NMR (300 MHz, D₂O): δ 7.21(2H, d), 7.15(2H, d),2.51(2H,t), 2.45(1H, m), 2.10(2H, t), 1.9-1.3(14H, m)

[0098] Compound XXVII—¹H NMR (300 MHz, DMSO-d₆): δ 9.75 (1H,s), 7.5(2H,d), 7.1 (2H,d), 2.5 (3H,q), 2.05 (3H,t), 1.6 (10H,m), 1.1 (5H,m),0.8 (3H,t)

[0099] Compound XXVIII—¹H NMR (300 MHz, DMSO-d₆): δ 9.82(1H, s),7.49(2H, d), 7.06(2H,d), 2.48(2H, t), 2.32(1H, m), 2.09(2H, t), 1.71(8H,m), 1.29(6H, m)

[0100] Compound XXIX—¹H NMR (300 MHz, DMSO-d₆): δ 10.0 (1H,s), 7.5(2H,d), 7.05 (2H,d), 2.5 (3H,m), 2.15 (2H,d), 1.85 (2H,t), 1.65 (8H,m),1.2 (3H,m), 1.90(2H,q)

[0101] Compound XXX—¹H NMR (300 MHz, DMSO-d₆): δ 9.85 (1H,d), 7.5(2H,d), 7.05 (2H,d), 2.45 (3H,m), 1.9 (2H,t), 1.7 (6H,m), 1.4 (4H,m),0.9 (3H,dd)

[0102] Compound XXXIII—¹H NMR (300 MHz, DMSO-d₆): δ 11.95(1H, s),2.2(2H, m), 1.8(2H, m), 1.4(10, br m), 0.83(3H, d) Compound XXXIV—Anal.Calcd for C₁₅H₁₉NO₃: C 68.96, H 7.26, N5.36, Found: C 68.75, H 7.24, N5.30. ¹H NMR (300 MHz, D₂O): δ 7.71 (2H, d), 7.33(2H, d), 2.06(2H, d),1.52(6H, m), 1.01 (3H, m), 0.84(2H, m)

[0103] Compound XXXV—Anal. Calcd for C₁₄H₁₀NO₃Cl: C, 60.96, H, 3.63, N,5.08 Found: C, 60.42, H, 3.64, N, 4.94. ¹H NMR (300 MHz, DMSO-d₆): δ10.85 (1H,s), 7.95 (2H,d), 7.85 (2H,d), 7.55 (4H,m)

[0104] Compound XXXVI—Anal. Calcd for C₁₆H₂₁NO₃: C 69.79, H 7.70, N5.08, Found: C 69.38, H 7.85, N 4.85. ¹H NMR (300 MHz, DMSO-d₆): δ10.0)1H, s), 7.45(2H, d), 7.10(2H, d), 3.18(2H, s), 2.15(2H, d),1.67(6H, br m), 1.17(3H, m), 0.95(2H, m)

[0105] Compound XXXVII—¹H NMR (300 MHz, DMSO-d₆): δ 12.25(1H, s),9.8(1H,s), 7.5(2H, d), 7.15(2H, d), 3.5(2H, s), 2.3(1H, m), 1.8(4H, m),0.3(6H, m)

[0106] Compound XXXVIII—Anal. Calcd for C₁₇H₁₅NO₃: C, 72.58, H, 5.39, N,4.98 Found: C, 72.34, H, 5.21, N, 4.93. ¹H NMR (300 MHz, DMSO-d₆): δ10.2 (1H,s), 7.6 (5H,m), 7.4 (3H,q), 7.2 (2H,d), 6.85 (1H,d), 3.5 (2H,s)

[0107] Compound XL—¹H NMR (300 MHz,DMSO-d₆): δ 8.6 (1H,m), 7.8 (2H,m),7.25 (5H,m), 7.1 (2H,dd), 4.25 (2H,d), 3.5 (2H,s)

[0108] Compound XLI—Anal. Calcd for C₁₅H₁₃NO₃. 0.27 H2O: C, 70.57, H,5.14, N, 5.49 Found: C, 69.24, H, 5.48, N, 5.37. ¹H NMR (300 MHz,DMSO-d₆): δ 10.25 (1H,s), 8.0 (2H,d), 7.7 (2H,d), 7.55 (3H,m), 7.25(2H,d), 3.5 (2H,s)

[0109] Compound XLII—¹H NMR (300 MHz, DMSO-d₆): δ 11.89(1H, s), 7.58(1H,s), 2.95(2H, t), 2.16(3H, m), 1.73(2H, t), 1.40(14H, m), 1.20(2H, t)

EXAMPLE 2

[0110] Compound IX was prepared as follows:

[0111] A solution of 4-phenylbutyryl chloride (10.20 g, 56 mmol) intetrahydrofuran (30 mL) was added dropwise to a mixture of4-(4-aminophenyl)butyric acid (10.00 g, 56 mmol, 1.0 equiv.),triethylamine (8.50 mL, 62 mmol, 1.1 equiv.) and tetrahydrofuran (100mL) at 10° C. The reaction was stirred at 10° C. for 1 hour and 25° C.for 3 hours. The solvent was then evaporated, and the residue wasdissolved in ethyl acetate (150 mL). After washing the ethyl acetatelayer with aqueous hydrochloric acid (1M, 3×100 mL) and water (2×100mL), the organic layer was dried and evaporated. The resultant residuewas recrystallized from acetonitrile-water to give IX as a pale yellowsolid (11.69 g, 65%).

[0112] Properties are listed below.

[0113]¹H NMR (300 MHz, alkaline D₂O) δ: 7.05 (2H, m), 6.94 (4H, m), 6.85(3H, m), 2.30 (4H, m) 2.01 (4H, m), 1.61 (4H, m). Anal. Calcd forC₂₀H₂₃NO₃: C, 73.81; H, 7.13; N, 4.30. Found: C, 73.53; H, 7.13; N,4.25.

[0114] Similar procedures were used to prepare compounds XV, XVII, XX,and XXI.

[0115] Properties are listed below.

[0116] Compound I—¹H NMR (300 MHz,D₂O): δ 7.75 (2H,q), 7.55 (1H,m), 7.45(2H,m), 7.35 (2H,dd), 7.2 (2H,dd), 2.55 (2H,m), 2.1 (2H,t), 1.75 (2H,m)

[0117] Compound III—Anal. Calcd for C₁₇H₁₆NO₃Cl: C, 64.26, H,5.07,N,4.41 Found: C, 63.29, H, 5.12, N, 4.19. ¹H NMR (300 MHz, DMSO-d₆): δ12.1 (1H,s), 10.4 (1H,s), 7.7 (2H,d), 7.6 (2H,d), 7.45 (2H,m), 7.2(2H,q), 2.6 (2H,m), 2.2 (2H,m), 1.8 (2H,m)

[0118] Compound IV—Anal. Calcd for C₁₇H₁₆NO₃F: C, 67.76, H, 5.35, N,4.65 Found: C, 67.15, H, 5.33, N, 4.46. ¹H NMR (300 MHz, DMSO-d₆): δ12.05 (1H,s), 10.35 (1H,s), 7.6 (4H,m), 7.3 (2H,q), 7.15 (2H,q), 2.6(2H,t), 2.2 (2H,t), 1.8 (2H,m)

[0119] Compound VII—¹H NMR (300 MHz, D₂O): δ 7.12(3H, m), 6.88(2H, s),6.67(5H, br m), 6.26(1H, d), 2.18(2H, t), 1.96(2H, t), 1.50(2H, q)

[0120] Compound VIII—¹H NMR (300 MHz, D₂O): δ 6.9 (9H,m), 2.6 (2H,t),2.3 (4H,t), 2.0 (2H,q), 1.6 (2H,m)

EXAMPLE 3

[0121] Compound XXIV was prepared as follows:

[0122] N-hydroxysuccinamide (8.86 g, 77.00 mmol, 1.1 equiv.) anddicyclohexylcarbodiimide (15.88 g, 77.00 mmol, 1.1 equiv.) were added toa solution of 3-(4-fluorobenzoyl)propionic acid (13.73 g, 70.00 mmol, 1equiv.) in dimethylformamide (250 mL). The reaction was stirred at 25°C. under nitrogen for 12 hours. The solution was diluted with water (500mL) and extracted with chloroform (250 mL). The organic layer was driedand filtered. Glacial acetic acid (5 mL) was added to the filtrate, andthis mixture stirred for 1 hour. The resulting chloroform solution waswashed with sodium bicarbonate (250 mL) and water (250 mL) and driedover magnesium sulfate. After filtration, 4-(4-aminophenyl)butyric acid(1 2.5 g, 70.00 mmol, 1 equiv.) and triethylamine (16 mL) were added tothe filtrate. The resulting mixture was stirred at 25° C. overnight, andit was then acidified with hydrochloric acid (250 mL) and lyophilized toyield XXIV as a white solid. (3.50 g, 14%).

[0123] Properties are listed below.

[0124]¹H NMR (300 MHz, DMSO-d₆) δ: 12.05 (H, br s), 9.95 (1H, s), 8.10(2H, t), 7.50 (2H, d), 7.35 (2H, t), 7.10 (1H, d), 2.70 (2H, t), 2.20(2H, t), 1.75 (2H, m). Anal. Calcd for C₂₀H₂₀NO₄F: C, 67.02; H, 5.62; N,3.90. Found: C, 67.08; H, 5.60; N, 3.86.

[0125] Similar procedures were used to prepare compound XLIII and XLIV.Properties are listed below.

[0126] Compound XLIII—Anal. Calcd for C₂₂H₂₇NO₃ 0.083 H2O: C, 74.44, H,7.73, N, 3.95 Found: C, 73.96, H, 7.73, N, 4.26. ¹H NMR (300 MHs,DMSO-d₆): δ 12.71 (1H,s), 8.2 (1H,q), 7.1 (9H,m), 4.4 (1H,m), 3.6(1H,m), 3.0 (1H,m), 2.85 (1H,m), 2.4 (1H,q), 1.8 (1H,m), 1.3 (2H,d),1.15 (1H,d), 0.85 (6H,d)

[0127] Compound XLIV—Anal. Calcd for C₂₂H₁₇NO₄F₂: C, 66.49, H, 4.32, N,3.53 Found: C, 66.14, H, 4.29, N, 3.33. ¹H NMR (300 MHz, DMSO-d₆): δ8.05 (1H,s), 7.5(2H,m), 7.35 (1H,m), 7.2(7H,m), 7.0 (1H,d), 4.7 (1H,m),3.2 (1H, dd), 3.05 (1H, m)

EXAMPLE 4

[0128] Compound XXXII was prepared as follows:

[0129] 1-oxaspiro(2.5)octane (3.76 g, 33.48 mmol, 1.2 equiv.) andaluminum chloride (0.36 g, 2.70 mmol, 0.1 equiv.) were added to asuspension of 4-(4-aminophenyl)butyric acid (5.00 g, 27.90 mmol, 1equiv.) in toluene (100 mL). The mixture was refluxed under argonovernight. After being cooled to room temperature, the toluene wasfiltered, and the residue was washed with ethyl acetate (ca. 100 mL).The combined filtrate was evaporated to yield a brown gum. The gum wasdissolved with ethyl acetate (250 mL). It was then washed with water(3×100 mL) and dried. After removal of the solvent, the residue waspurified by column chromatography (30% to 70% ethyl acetate/hexanes),and the collected product was recrystallized from ethyl acetate-hexanesto give XXXII as yellow solid (0.8 g, 10%).

[0130] Properties are listed below.

[0131]¹H NMR (300 MHz, DMSO-d₆) δ: 6.85 (2H, d, J=8.4 Hz), 6.53 (2H, d,J=8.4 Hz), 5.00 (1H, br s), 2.88 (2H, s), 2.39 (2H, t, J=7.2 Hz), 2.15(2H, t, J=7.4 Hz), 1.69 (2H, m), 1.45 (10H, m). Anal. Calcd for C₁₇H₂₅NO₃: C, 70.07; H, 8.65; N, 4.81. Found: C, 70.20; H, 8.69; N, 4.67.

EXAMPLE 5

[0132] Compound XXXIX was prepared as follows:

[0133] N-hydroxysuccinimide (7.72 g, 67.50 mmol, 1.1 equiv.) anddicyclohexylcarbodiimide (13.96 g, 67.50 mmol, 1.1 equiv.) were added toa solution of N-(2-phenylbutyryl)-4-(aminophenyl)butyricacid (20.00 g,61.40 mmol, 1.0 equiv.) in tetrahydrofuran (400 mL). The reaction wasstirred overnight at 25° C. The urea formed was removed by filtration.Glacial acetic acid (5 mL) was added to the filtrate and stirred for 2hours. The solvent was then evaporated to yield an oil. The oil wasredissolved in chloroform (300 mL), and the resultant solution waswashed successively with saturated sodium bicarbonate (2×200 mL) andwater (200 mL). The combined aqueous layers were extracted withchloroform (100 mL) to give a filtrate (a total volume of 500 mL)containing the Osu ester of N-(2-phenylbutyryl)-4-(4-aminophenyl)butyricacid.

[0134] A mixture of phenylglycine O-methylester hydrochloride (12.40 g,61.40 mmol, 1.0 equiv.) and triethylamine (35 mL) in chloroform (100 mL)was charged to an addition funnel. The mixture was added dropwise to thechloroform solution of the Osu ester prepared above. The reaction wasstirred at 25° C. for 24 h. The resulting solution was washed withaqueous hydrochloric acid (2×500 mL) and water (500 mL). The aqueouslayer was back extracted with chloroform (50 mL). The combinedchloroform layers were dried and evaporated to yield an oil. Aqueoussodium hydroxide (2M, 200 mL) was added to the oil, and the mixture washeated to 100° C. for 2 h. After being cooled to room termerature, thesolution was acidified with hydrochloric acid (2 M) to pH 2.5. Theprecipitate was filtered, washed with hydrochloric acid (100 mL) andwater (100 mL) to give XXXIX as an off white solid (15.2 g, 54%).

[0135] Properties are listed below.

[0136]¹H NMR (300 MHz, DMSO-d₆) δ: 12.70 (1H, br s), 10.00 (1H, s), 8.55(1H, d), 7.50 (2H, d), 7.33 (10H, m), 7.06 (2H, d), 5.32 (1H, d), 3.54(1H, m), 2.49 (2H, overlapped with DMSO), 2.16 (2H, m), 2.05 (1H, m),1.73 (3H, m). 0.83 (3H, t). Anal. Calcd for C₂₈H₃₀N_(2O) ₄: C, 73.30; H,6.61; N, 5.73; Found: C, 72.54; H, 6.60; N, 5.73.

EXAMPLE 6 In Vivo Evaluation of Interferon in Rats

[0137] Dosing compositions were prepared by mixing the modified aminoacid compounds and interferon α2 as listed in Table 1 below in a Trizma®hydrochloride buffer solution (Tris-Hcl) at a pH of about 7-8. Propyleneglycol (0-25%) was added as a solubilizing agent, if necessary.

[0138] Rats were orally or intraduodenally (ID) administered the dosingcompositions, and delivery was evaluated by an ELISA assay for humaninterferon α-2b.

[0139] Results are illustrated in Table 1 below. TABLE 1 Oral Deliveryof Interferon Carrier Dose Interferon Dose Mean Peak Serum LevelsCarrier (mg/kg) (μg/kg) of Interferon (ng/mL) XXVI 300 1000 6710 +/−6658 XXXVII 160 1000 1025 +/− 276  XXVII 300 1000 3642 +/− 5895 XXXIV400 1000 11341 +/− 8793  400 500 565 +/− 515 XXXIV (ID) 400 100 1775 +/−1023 XXIX 600 100 3510 +/− 2171 I 300 1000 10072 +/− 3790  I (ID) 250 50843 +/− 669 I 80 250 1369 +/− 1164 VI 300 1000 8213 +/− 3077 VI 600 10008428 +/− 5001 VI (ID) 1000 15469 +/− 6712  XXXVI 400 1000 43961 +/−14910 XIV 800 1000 5518 +/− 2718 VII 600 1000 5568 +/− 3771 XXVII 3001000 41966 +/− 19688 VIII 300 1000 1753 +/− 1529 XVIII 300 1000 19809+/− 26107 XXX 300 1000 3910 +/− 3221 XL 300 1000 12661 +/− 10933 none 01000 688 +/− 173

EXAMPLE 7 In Vivo Evaluation of Salmon Calcitonin in Rats

[0140] Dosing compositions were prepared and dosed using the modifiedamino acid compound carriers and salmon calcintonin as listed in Table 2below. The concentration of calcitonin in each composition was 2.5μg/ml. Each rat was administered 2 ml/kg of dosing composition.

[0141] Blood samples were collected serially from the tail artery. Serumcalcium was determined by testing with a Calcium Keto (Sigma ChemicalCo.—St. Louis, Mo.)

[0142] Results are illustrated in Table 2 below.

EXAMPLE 8 In Vivo Evaluation of Salmon Concentration in Rats

[0143] A dosing composition was prepared using 400 mg of compound VIwith 2.9 ml of 25% aqueous propylene glycol. The resultant solution wasstirred, and the pH was adjusted to 7.2 with sodium hydrochloride(1.010). Water was added to bring the total volume to 2.0 ml and a finalmodified amino acid concentration of 200 mg/ml. Salmon calcitonin (10mg) was added.

[0144] This composition was dosed as described in Example 7 above.

[0145] Results are illustrated in Table 2 below. TABLE 2 Oral Deliveryof Calcitonin Carrier Dose Dose Drug Mean Peak Serum Levels Carrier(mg/kg) (μg/kg) of Interferon (ng/mL) XXVI 10 300 −18 +/− 6 XXVIII 10200 −14 +/− 6 I 10 200 −16 +/− 8 VII 10 200 −13 +/− 8 VI 10 200  −29 +/−14 30 10 −13 +/− 4 10 30 −24 +/− 9

EXAMPLE 9 In Vivo Evaluation of Recombinant Human Growth Hormone (rhGh)in Rats

[0146] Dosing compositions were prepared with modified amino acids in aphosphate buffer at a pH of about 7-8 and rhGH as listed in Table 3below.

[0147] Rats were administered the compositions by oral gavage,intraduodenal administration (ID), or colonic administration (IC).

[0148] Results are illustrated in Table 3 below. TABLE 3 Oral Deliveryof rhGH Carrier Dose Dose Drug Mean Peak Serum Levels Carrier (mg/mL)(mg/mL) of rhGH (ng/mL) XXVI 500 6 −127 +/− 40  XXVII 500 6 −64 +/− 7 VI 150 6 −33 +/− 13  VI (ID) 200 3 −103 +/− 85  VI (IC) 50 1.5 −98 +/−19  II 400 6 55 +/− 36 XXX 400 6 66 +/− 37 XLV 400 6 28 +/− 9  IV 300 642 +/− 29 XLIII 300 6 63 +/− 45 X 250 6 37 +/− 12 XXXII 200 6 44 +/− 36none 0 6 <10

EXAMPLE 10

[0149] In Vivo Evaluation of Heparin in Rats

[0150] 900 mg of modified amino acid were dissolved in 3 ml of propyleneglycol, and 0.299 gram of sodium heparin was dissolved in 3 ml of water.The two solutions were mixed by vortex. Sodium hydrochloride was addedto the resultant mixture until a solution was obtained. The pH was thenadjusted to 7.4±0.5 with concentrated hydrochloric acid. The finalsolution was sonicated at 40 C for 30 minutes to yield a dosingsolution.

[0151] The dosing solution was administered by oral gavage to fastedrats.

[0152] Blood samples were collected by cardiac puncture following theadministration of ketamine (44 mg/kg). Heparin activity was determinedby utilizing the activated partial thromboplastin time (APTT) accordingto the method of Henry, J. B., Clinical Diagnosis and Management byLaboratory Methods; Philadelphia, Pa.; WB Saunders (1979). Results areillustrated in Table 4 below. TABLE 4 Oral Delivery of Heparin CarrierMean Peat APTT (sec) # Animals Responding XXI 166 +/− 35  5/5 IX 102 +/−33  34/35 VI 96 +/− 29 10/10 XLI 90 +/− 49 5/5 XXXV 73 +/− 16 4/4 VII 52+/− 24 17/20 XV 67 +/− 30 4/5 XX 59 +/− 42 4/4 VII 58 +/− 28 14/15 XLII45 +/− 14 5/5 XXXIII 44 +/− 28 12/20 XXVII 44 +/− 15 18/20 V 42 +/− 164/5 III 41 +/− 18  8/10 II 41 +/− 24 3/5 XXXIX 40 +/− 17  5/10 XIX 37+/− 11 4/5 XXII 36 +/− 19  6/11 XXVIII 35 +/− 9  3/5 none 20.7 +/− 0.17100/100

EXAMPLE 11

[0153] Low molecular weight heparin was dosed according to the method ofExample 10.

[0154] The above mentioned patents, applications, test methods, andpublications are hereby incorporated by reference in their entirety.

[0155] Many variations of the present invention will suggest themselvesto those skilled in the art in light of the above detailed description.All such obvious variations are within the full intended scope of theappended claims.

What is claimed is:
 1. A compound selected from the group consisting of

or salts thereof.
 2. A poly amino acid comprising at least one compoundselected from the group consisting of

or salts thereof.
 3. A poly amino acid as defined in claim 2, comprisinga peptide.
 4. A composition comprising a. an active agent; and b. acompound as defined in claim
 1. 5. A composition comprising a. an activeagent; and b. a poly amino acid as defined in claim
 2. 6. A compositionas defined in claim 5, wherein said poly amino acid comprises a peptide.7. A composition as defined in claim 4, wherein said active agentcomprises a biologically active agent.
 8. A composition as defined inclaim 7, wherein said biologically-active agent is selected from thegroup consisting of a peptide, a mucopoly-saccharide, a carbohydrate, alipid, a pesticide, or any combination thereof.
 9. A composition asdefined in claim 8, wherein said biologically-active agent is selectedfrom the group consisting of human growth hormone, bovine growthhormone, growth hormone-releasing hormone, an interferon,interleukin-II, insulin, heparin, calcitonin, erythropoietin, atrialnaturetic factor, an antigen, a monoclonal antibody, somatostatin,adrenocorticotropin, gonadotropin releasing hormone, oxytocin,vasopressin, cromolyn sodium, vancomycin, desferrioxamine (DFO), or anycombination thereof.
 10. A composition as defined in claim 5, whereinsaid active agent comprises a biologically active agent.
 11. Acomposition as defined in claim 10, wherein said biologically-activeagent is selected from the group consisting of a peptide, amucopoly-saccharide, a carbohydrate, a lipid, a pesticide, or anycombination thereof.
 12. A composition as defined in claim 11, whereinsaid biologically-active agent is selected from the group consisting ofhuman growth hormone, bovine growth hormone, growth hormone-releasinghormone, an interferon, interleukin-II, insulin, heparin, calcitonin,erythropoietin, atrial naturetic factor, an antigen, a monoclonalantibody, somatostatin, adrenocorticotropin, gonadotropin releasinghormone, oxytocin, vasopressin, cromolyn sodium, vancomycin,desferrioxamine (DFO), or any combination thereof.
 13. A composition asdefined in claim 6, wherein said active agent comprises a biologicallyactive agent.
 14. A composition as defined in claim 13, wherein saidbiologically-active agent is selected from the group consisting of apeptide, a mucopoly-saccharide, a carbohydrate, a lipid, a pesticide, orany combination thereof.
 15. A composition as defined in claim 14,wherein said biologically-active agent is selected from the groupconsisting of human growth hormone, bovine growth hormone, growthhormone-releasing hormone, an interferon, interleukin-II, insulin,heparin, calcitonin, erythropoietin, atrial naturetic factor, anantigen, a monoclonal antibody, somatostatin, adrenocorticotropin,gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium,vancomycin, desferrioxamine (DFO), or any combination thereof.
 16. Adosage unit form comprising (A) a composition according to claim 4; and(B) (a) an excipient, (b) a diluent, (c) a disintegrant, (d) alubricant, (e) a plasticizer, (f) a colorant, (g) a dosing vehicle, or(h) any combination thereof.
 17. A dosage unit form according to claim16, comprising a tablet, a capsule, or a liquid.
 18. A dosage unit formcomprising (A) a composition according to claim 5; and (B) (a) anexcipient, (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) aplasticizer, (f) a colorant, (g) a dosing vehicle, or (h) anycombination thereof.
 19. A dosage unit form according to claim 18,comprising a tablet, a capsule, or a liquid.
 20. A dosage unit formcomprising (A) a composition according to claim 6; and (B) (a) anexcipient, (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) aplasticizer, (f) a colorant, (g) a dosing vehicle, or (h) anycombination thereof.
 21. A dosage unit form according to claim 20,comprising a tablet, a capsule, or a liquid.
 22. A method foradministering a biologically-active agent to an animal in need of saidagent, said method comprising administering orally to said animal acomposition as defined in claim
 4. 23. A method for administering abiologically-active agent to an animal in need of said agent, saidmethod comprising administering orally to said animal a composition asdefined in claim
 5. 24. A method for administering a biologically-activeagent to an animal in need of said agent, said method comprisingadministering orally to said animal a composition as defined in claim 6.25. A method for preparing a composition, said method comprising mixing:(A) at least one biologically-active agent; (B) at least one compound asdefined in claim 1; and (C) optionally a dosing vehicle
 26. A method forpreparing a composition, said method comprising mixing: (A) at least onebiologically-active agent; (B) at least one poly amino acid as definedin claim 2; and (C) optionally a dosing vehicle
 27. A method forpreparing a composition, said method comprising mixing: (A) at least onebiologically-active agent; (B) at least one peptide as defined in claim3; and (C) optionally a dosing vehicle.